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European Heart Journal (2013) 34, 1708–1715 Expert position paper on the use of proton pumpinhibitors in patients with cardiovascular diseaseand antithrombotic therapy Stefan Agewall1*, M. Cattaneo2, J.P. Collet3, F. Andreotti4, G.Y.H. Lip5,F.W.A. Verheugt6, K. Huber7, E.L. Grove8, J. Morais9, S. Husted10, S. Wassmann11,G. Rosano12, D. Atar1, A. Pathak13, K. Kjeldsen14, and R.F. Storey15, on behalf of ESCWorking Group on Cardiovascular Pharmacology and Drug Therapy and ESC Working Group on Thrombosis 1Department of Cardiology, Oslo University Hospital, Oslo University, Oslo, Norway; 2Medicina 3, Ospedale San Paolo. Dipartimento di Scienze della Salute, Universita degli Studidi Milano, Milan, Italy; 3Universite´ Pierre et Marie Curie-INSERM U 937 Institut de Cardiologie Groupe Hospitalier Pitie´-Salpeˆtrie re (APHP) 47-83, Bd de l'hopital, 75013, Paris,France; 4Department of Cardiovascular Sciences, Catholic University Hospital, Rome, Italy; 5University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom; 6Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG) Amsterdam, Netherlands; 73rd Medical Department, Cardiology and EmergencyMedicine, Wilhelminenhospital, Vienna, Austria; 8Department of Cardiology, Aarhus University Hospital, Skejby, Denmark; 9Servic¸o de Cardiologia, Centro Hospitalar Leiria Pombal,Leiria, Portugal; 10Department of Cardiology, A ˚ rhus University Hospital, A˚rhus, Denmark; 11Department of Cardiology, Isar Heart Center, Isar Kliniken, Munich, Germany; 12Department of Medical Sciences, IRCCS San Raffaele Pisana, Via della Pisana, 235 Roma, Italy; 13CHU et Faculte´ de Me´decine de Toulouse, Institut des Maladies Me´taboliques etCardiovasculaires (U104), Institut National de la Sante´ et de la Recherche Me´dicale, Universite´ Toulouse III Paul Sabatier, Toulouse, France; 14The Heart Centre, CopenhagenUniversity Hospital (Rigshospitalet) and The Faculty of Medicine, Aalborg University, Copenhagen and Aalborg, Denmark; and 15Department of Cardiovascular Science, University ofSheffield, Sheffield, UK Received 8 November 2012; revised 13 December 2012; accepted 20 January 2013; online publish-ahead-of-print 20 February 2013 has been reported that concomitant use of PPIs reduces the pro-tective efficacy of ASA in patients with ischaemic heart disease.
The ESC NSTEMI and STEMI guidelinesand an ACCF/ACG/ A case – control study investigated the antiplatelet effect of ASA in AHA consensus documentrecommend treatment with proton 418 ASA-treated CVD patients, 54 of whom were also treated pump inhibitors (PPIs) in patients treated with dual antiplatelet with Patients receiving PPIs had reduced antiplatelet effect treatment (DAPT) during the initial phase of an acute coronary of ASA, as shown by greater residual platelet aggregation syndrome (ACS) (ESC Class 1A recommendation), particularly in responses. However, interaction between PPI and ASA is contro- patients with a history of GI bleeding or peptic ulcer. Several versial.Potential clinical implications of these findings were explored studies have raised concerns that many PPIs, especially omepra- by a registry study in a large population of ASA-treated patients with zole, might diminish the antiplatelet effects of clopidogrel, most first time myocardial infarcEven after adjusting for baseline vari- likely through inhibition of CYP2C19 and, consequently, the con- ables with multivariate analysis and propensity score matching, PPI version of clopidogrel into its active metabolite.
use was still significantly associated with 50% more ischaemic car- The aim of this position paper is to review the pharmacokinetic diovascular events. A sensitivity analysis showed no increase in risk background of the interactions between these drugs, and their related to the use of H2 receptor block consequences on clinical outcomes, and to present suggestions Suggested explanations for the observed interaction of PPIs with for management of this important issue.
ASA in cardiovascular patients are (i) the reduced gastric acidityinhibiting the uptake of the weakly acidic ASA, (ii) the worse base- Acetylsalicylic acid and proton line characteristics of patients with concomitant GI disorders, and (iii) the play of chance. The studies on ASA uptake in relation togastric acidity show negative findings.Even with multivariate Several agents widely used in patients on acetylsalicylic acid (ASA) and propensity score matching analyses, the existence of unrecog- may interact with the antiplatelet effects of ASA, but none through nized confounding variables can never be excluded in the absence the CYP2C9 pathway by which ASA is metabolized. Recently, it of randomized controlled trials.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Tel: +47 22 89 46 55, Fax: +47 22 89 42 59, Email: Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected] Expert position paper on the use of PPIs in CVD and antithrombotic drugs Conclusion: acetylsalicylic acid and lansoprazole (Ki: 0.4 – 1.5 mM), omeprazole (Ki: 2 – 6 mM), and proton pump inhibitors esomeprazole (Ki: 8 mM) down to weaker ones such as rabepra-zole (Ki: 17 – 21 mM) and pantoprazole (Ki: 14 – 69 mM).A PPI So far, there are insufficient data to suggest a clinical interaction with less CYP2C19 inhibitory capacity (e.g. pantoprazole) may rep- between PPI use and the protective efficacy of ASA in patients resent a more optimal treatment option than a PPI with high with CVD. Use of PPIs is recommended for the prevention of CYP2C19 inhibitory capacity (e.g. omeprazole) in patients who gastric ulceration in ASA-treated patients at high risk of GI require both clopidogrel and a PPI (Figures and Studies showing no effect of proton pump Clopidogrel and proton pump inhibitors on clinical outcome Several publications show no clear impact of PPIs on the clinical– An analysis of the TRITON-TIMI 38 study Clopidogrel is a pro-drug that is metabolized in a two-step oxida- showed that clopidogrel-treated patients on omeprazole had tive process(Figure ). In the first step, the CYP isozymes similar outcomes compared with patients treated with pantopra- CYP1A2, CYP2B6, and CYP2C19 form 2-oxo-clopidogrel that is zole or other Moreover, the prospective randomized then oxidized to the clopidogrel active metabolite by CYP2B6, COGENT trial,the only RCT that had been designed to CYP2C19, and CYP3A4. CYP2C19 contributes to 40% of the test the hypothesis of PPI – clopidogrel interaction on MACE, hepatic conversion of clopidogrel into the short half-life active me- demonstrated that omeprazole reduces GI events in patients on tabolite that irreversibly binds to the platelet P2Y12 receptor.
clopidogrel and ASA without any apparent impact on cardio- The activity of CYP2C19 may be altered by xenobiotics such as vascular events, although rates of ischaemic events were low and PPIs, which are CYP2C19 substrates and interact with clopidogrel the study was not powered to exclude a relevant interaction in metabolism as a result of competitive antagonism. The interaction higher-risk patients. The product was purposefully formulated to between PPIs and clopidogrel depends on the potency of each PPI retard the dissolution and absorption of omeprazole, thereby re- to inhibit CYP2C19, ranging from stronger inhibitors such as ducing the risk of interaction with clopidogrel.
Figure 1 Two-step metabolic activation of clopidogrel. Bioavailability of the pro-drug is determined by intestinal absorption, which might belimited by the efflux pump MDR1 (encoded by ABCB1). Subsequently, 85% of the pro-drug is converted into inactive metabolites by ubiquitousesterases. The remaining 15% is converted into a thiol-containing active metabolite through two-step oxidations that involve several cyto-chrome P450 enzymes. The first oxidative step is catalysed by CYP2C19, CYP1A2 and CYP2B6 isoenzymes, producing the intermediate 2-oxo-clopidogrel. The second step is mediated by CYP3A4, CYP2B6, CYP2C19, and CYP2C9 and yield the bioactive metabolite, the cis-thiol isomerwhich irreversibly binds to platelet P2Y12 receptors inhibits ADP-induced platelet activation.
S. Agewall et al.
Similarly, in a recent studconcomitant use of a PPI in analysis. Importantly, there was no significant difference between patients receiving DAPT after coronary stenting was not an inde- pantoprazole and other PPIs, including omeprazole, on clinical pendent predictor of stent thrombosis although PPI-treated patients had higher mortality. This was explained by the higherrisk profile of PPI-treated patients at baseline. Moreover, theworse clinical outcome of PPI-treated patients in large registry Studies indicating potential effects of studies might be explained by confounding, because the sicker proton pump inhibitors on clinical patients more frequently received gastric protection with PPIs.
Analysis of a registry of consecutive patients undergoing coronarystenting did not demonstrate an association between the use of Post hoc analyses from large registries suggested an increased rate PPIs and an increased risk of adverse clinical outcomes after of MACE when DAPT and PPIs were combine– In a adjusting for potential confounders and a propensity score meta-analysis, concomitant PPI and DAPT use was associatedwith an increased risk of cardiovascular events but had no influ-ence on mortaliAnother meta-analysis demonstrated thatpatients on PPIs and DAPT had an increased MACE event rateand mortality. This finding was observed only in high-riskpatientsHo et al.demonstrated that concomitant use of clo- pidogrel and PPIs was associated with an increased risk for re-current ACS but not for all-cause mortality, while Juurlinket aldemonstrated in a population-based nested case –control study that PPIs, except pantoprazole, are associatedwith re-infarction after treatment for acute myocardial infarction.
Furthermore, patients receiving PPIs frequently represent a high-risk co-morbid population: Indeed, patients on concomitant PPItreatment in studies showing adverse effects of PPIs had morefrequently co-morbidities including diabetes, renal dysfunction,hypertension, a history of myocardial infarction, and heartfailureSuch co-morbidities are obviously associated withworse clinical outcome. In the recent Trilogy studexaminingpatients with unstable angina or myocardial infarction withoutST-segment elevation who were not planned to undergo revas- Figure 2 Pharmacodynamic interactions between proton cularization, prasugrel did not significantly reduce the frequency pump inhibitors and clopidogrel: a metabolic drug – drug inter- of the primary endpoint, when compared with clopidogrel.
action exists between clopidogrel and omeprazole but not However, in the subgroup treated with PPI at randomization, between clopidogrel and pantoprazole.
the event rate was significantly lower in the prasugrel group Figure 3 The proton pump inhibitor treatment algorithm in patients with acute coronary syndrome. ACS, acute coronary syndrome;GI, gastrointestinal; PPI, proton pump inhibitor.
Expert position paper on the use of PPIs in CVD and antithrombotic drugs compared with the clopidogrel group (14.6 and 23.8%, respect- Conclusion: prasugrel and proton pump ively, P , 0.02).
The study entitled ‘Double the Dose of Clopidogrel or Switch to Current data do not support the need to avoid concomitant use of Prasugrel to Antagonize Proton Pump Inhibitor Interaction'(DOSAPI) PPIs, when clinically indicated, in patients receiving prasugrel.
aimed to determine the optimal therapeutic strategy for patients withCVD chronically treated with clopidogrel 75 mg/day requiringco-administration of a PPI for treatment/prevention of GI ulceration Ticagrelor and proton pump (NCT01175200). The results were recently presented as an abstract.
In summary, the effect of a double clopidogrel maintenance dose on platelet inhibition was significantly attenuated by the co-administration CYP2C enzymes are not known to be involved in the metabolism of lansoprazole as opposed to prasugrel 10 mg.
of ticagrelor and clearance is predominantly through CYP3A4.Consequently, it is not expected that PPIs will have any significant Conclusion: clopidogrel and proton pump inhibitors pharmacokinetic interaction with ticagrelor.
In the absence of large prospective randomized trials powered for In the PLATO PLATELET substudy, patients treated with a clinical outcome, there is concern that the higher event rates variety of PPIs in combination with ticagrelor had similar platelet observed for PPI-treated patients in observational studies and reactivity to patients receiving ticagrelor without A post meta-analyses might in part be explained by differences in baseline hoc analysis of the PLATO study was performed to assess clinical confounding variables.In summary, potential negative clinical outcomes of patients who did or did not receive a PPI in the impacts of some PPIs on the therapeutic efficacy of clopidogrel two treatment groups.A total of 6539 patients were treated are still controversial. In view of the pharmacokinetic data and incon- with PPIs at randomization compared with 12 060 patients who clusive clinical evidence, PPIs with weaker inhibition of CYP2C19 are were not. Patients treated with a PPI at randomization had preferred in combination with clopidogrel compared with those higher rates of ischaemic and bleeding events in both the ticagrelor with stronger inhibition such as omeprazole.
and clopidogrel groups but the treatment effect of ticagrelor com-pared with clopidogrel was not influenced by PPI use. These datasuggest that most likely there were unidentified confounding vari-ables responsible for the increased event rates in PPI-treated Prasugrel and proton pump patients rather than any adverse effect of PPIs per se on the thera- peutic efficacy of ticagrel In an open-label, four-period crossover study, the effects of lanso- Conclusion: ticagrelor and proton pump prazole on the pharmacokinetics and pharmacodynamics of prasu- grel and clopidogrel were assessed in healthy subjects given singledoses of prasugrel 60 mg and clopidogrel 300 mg with and without There is no evidence of any adverse interaction between ticagrelor concurrent lansoprazole 30 mg q.d. Lansoprazole did not signifi- and PPIs. The use of PPIs is recommended in ticagrelor-treated cantly affect the inhibition of platelet aggregation induced by prasu- patients who are at an increased risk of GI haemorrhage.
grel, but tended to decrease platelet aggregation by clopidogrel.In another study, the co-administration of lansoprazole with prasu- Warfarin and proton pump grel decreased the area-under-the-curve (AUC) and peak plasmalevels of prasugrel by 25 and 52%, respectively, suggesting an effect of PPI on prasugrel absorption.In a study of 104 high-risk and clinical evidence patients with ACS on treatment with prasugrel, the prevalence ofhigh on-treatment platelet reactivity was not significantly affected Proton pump inhibitors have been shown to reduce warfarin me- by the co-administration of PPI with pr tabolism and clearance leading to increased prothrombin time pro- A retrospective analysis of two trials comparing prasugrel with longation induced by wIn studies of rats, a neutral or basic clopidogrel, the PRINCIPLE-TIMI 44 trial and the TRITON gastric pH was associated with faster warfarin absorption from the TIMI-38 trial, revealed that: (i) the co-administration of PPI with pra- stomach into the plasma pool compared with an acidic pH, sugrel was associated with only a modest reduction in platelet aggre- whereas low pH was associated with warfarin precipitation on the gation after one loading dose (60 mg), while co-administration with gastric wall mucosa and with slower plasma Proton clopidogrel was associated with reduced platelet aggregation; (ii) no pump inhibitors may thus accelerate warfarin absorption. Proton association existed between PPI use and risk of the primary endpoint pump inhibitors and warfarin are both metabolized by hepatic CYP for patients with ACS treated with clopidogrel [adjusted hazard enzymes. Warfarin, acenocoumarol, and phenprocoumon are largely ratio (HR) 0.94, 95% CI: 0.80 – 1.11] or prasugrel (1.00, 0.84 – metabolized by CYP2CIn addition to inhibiting CYP2C19, As discussed above, the event rate was significantly lower PPIs may also induce CYP2C9 activity.Omeprazole, the oldest in the prasugrel group compared with the clopidogrel group in drug in the class of PPIs, is reported to have greater potential to the Trilogy study,in the subgroup treated with PPI at randomiza- alter CYP activity than the newer PPIs, such as pantoprazo tion, whereas the main study showed no significant benefit of Drug interaction studies in humans indicate that pantoprazole does S. Agewall et al.
phenprocoumon or warfarin and that the latter does not have rele- Oral factor Xa inhibitors and vant pharmacological effects on pantopr proton pump inhibitors Clinical evidence Only potent inhibitors and inducers of CYP3A4 and P-glycoproteininfluence the pharmacokinetics of rivaoxaban and apixaban and In healthy volunteers, a double-blinded randomized cross-over thus not – Data from the ROCKET-AF trial, comparing 10-day administration of dexlansoprazole once daily, compared rivaoxaban and warfarin in patients with atrial fibrillation, demon- with placebo, did not influence the peak plasma concentration strate the same rate of major bleeding in patients on rivaroxaban or AUC of warfarin nor INR values following a single dose of war- treatment compared with warfarin (target INR: 2 – 3), but a signifi- In 2755 Dutch patients receiving acenocoumarol mainten- cantly higher rate of GI bleeding was seen with rivaroxaban.At ance treatment, an observational follow-up found a significant baseline, 13% of patients were treated with a PPI, and the effi- hazard of excessive anticoagulation (INR ≥6) in those receiving cacy and safety of rivaroxaban compared with warfarin were not concomitant esomeprazole (HR: 1.99) or lansoprazole (HR: significantly influenced by this co-medication. In the ARISTOTLE 1.49), and a non-significant hazard for other PPIs, with no detect- stuapixaban reduced both the primary outcome of stroke able effect of the CYP2C19*2 or systemic embolism (by 21%) and major bleeding (by 31%) com-pared with warfarin (with target INR: 2 – 3) in patients with atrial Conclusion: warfarin and proton pump fibrillation. There was no difference in the risk of GI bleeding. Atbaseline, 18.5% of patients received gastric antacid drugs, but no specific data are available for this subpopulation of patients.
Proton pump inhibitors may accelerate absorption of warfarin, andomeprazole may influence vitamin K antagonists (VKAs)' pharma- Conclusion: oral factor Xa inhibitors and cokinetics more than newer PPIs. In clinical randomized studies, proton pump inhibitors the administration of a single dose of warfarin may have reduced The administration of PPIs to patients receiving oral FXa inhibitory the chance to detect potential PPI effects on INR values. On the drugs is unlikely to influence the pharmacokinetics of the drugs and other hand, the observational studies that suggest enhanced bleed- is warranted if an increased risk of GI bleeding is expected.
ing risk when PPIs are co-administered with VKAs may be subjectto selection biases. At present it is appropriate to monitor cau-tiously patients on VKA and PPI co-medication.
Summary and clinical implications Several mechanisms may explain why co-administration of PPIs Dabigatran and proton pump might reduce the cardiovascular benefits of antithrombotic drugs.
Most importantly, PPIs interact with key metabolic enzymes in the liver, such as CYP2C19, which is the principal enzyme respon- and clinical evidence sible for converting clopidogrel into its active metabolite. Anothermechanism may be related to the reduced efficacy of ASA and Dyspepsia is more common during treatment with dabigatran other drugs whose absorption depend on gastric pH. Importantly, compared with warfarin treatment.,Dyspepsia-like symptoms such an effect is likely to represent a class effect of PPIs, since all were not associated with an increased risk of major bleeding for PPIs affect gastric pH to approximately the same extent.
dabigatran-treated subjects; however, the probability of any bleed- Another scarcely investigated issue is the fact that PPIs, in add- ing increased slightly.Patients with dyspepsia related to dabiga- ition to reducing GI complications, may actually improve cardiovas- tran can alleviate symptoms by taking the drug with food or a cular outcome by optimizing compliance with antiplatelet large glass of water or by taking a PPI.Limited data are available therThis is important, because even short-term discontinu- on the detailed pharmacokinetics of dabigatran when a PPI is also ation of antiplatelet therapy may have ominous prognostic taken. Co-prescription with a PPI such as pantoprazole may mildly reduce dabigatran exposure and peak concentrations, although Although all PPIs are extensively metabolized by hepatic CYP these effects do not have any appreciable impact on the efficacy enzymes, there is some variation in the potential for drug interac- of dabigatran.In the RE-LY trial, concomitant use of PPIs tions because of differences in enzyme inhibition.Omeprazole, reduced drug exposure by 15%, but no significant impact on the first PPI on the market, may have greater potential to alter efficacy outcomes was observed.
CYP activity than newer PPIs, such as pantoprazole,yet nomajor differences between PPIs have been documented withrespect to the cardiovascular outcomes.
Conclusion: dabigatran and proton pump Still, potential interactions between clopidogrel and PPIs are controversial with less firm conclusions on clinical efficacy com- Proton pump inhibitors may be useful to alleviate dyspepsia related pared with measurements of platelet function. Pharmacodynamic, to dabigatran as well as reduce GI bleeding risk. Current evidence but not clinical, studies supports the use of newer PPIs, such as indicates that the mild reduction in dabigatran exposure related to pantoprazole, instead of omeprazoOn the other hand, PPIs PPI usage does not warrant any dose adjustment.
may potentiate VKA-induced anticoagulation, resulting in increased Expert position paper on the use of PPIs in CVD and antithrombotic drugs INR values and bleeding risk, most likely due to facilitated gastric Zahger D; ESC Committee for Practice Guidelines, Bax JJ, Auricchio A, absorption of warfarin. Therefore, patients treated with PPIs and Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C,Hasdai D, Hoes A, Knuuti J, Kolh P, McDonagh T, Moulin C, Poldermans D, VKAs in combination should be carefully monitored, with frequent Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Torbicki A, Vahanian A, measurements of INR, when treatment with a PPI is initiated or Windecker S; Document Reviewers, Windecker S, Achenbach S, Badimon L, Bertrand M, Bøtker HE, Collet JP, Crea F, Danchin N, Falk E, Goudevenos J,Gulba D, Hambrecht R, Herrmann J, Kastrati A, Kjeldsen K, Kristensen SD, The CRUSADE bleeding scorecan be used to determine the Lancellotti P, Mehilli J, Merkely B, Montalescot G, Neumann FJ, Neyses L, likelihood of adverse bleeding events in patients who have had Perk J, Roffi M, Romeo F, Ruda M, Swahn E, Valgimigli M, Vrints CJ, non-ST elevation ACS. This validated score can be used as an ob- Widimsky P. ESC Guidelines for the management of acute coronary syndromesin patients presenting without persistent ST-segment elevation: the Task Force jective means of stratifying risk of GI bleeding and thus judging the for the management of acute coronary syndromes (ACS) in patients presenting need for GI-protective medications such as PPIs.
without persistent ST-segment elevation of the European Society of Cardiology Currently available clinical outcomes data are mainly derived (ESC). Eur Heart J 2011;32:2999 – 3054.
2. Steg PG, James SK, Atar D, Badano LP, Lundqvist CB, Borger MA, Di Mario C, from retrospective studies, including registries, and, therefore, con- Dickstein K, Ducrocq G, Fernandez-Aviles F, Gershlick AH, Giannuzzi P, founding cannot be excluded; PPIs may represent a marker of car- Halvorsen S, Huber K, Juni P, Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW, diovascular risk rather than the cause of reduced efficacy of Valgimigli M, Van't Hof A, Widimsky P, Zahger D; ESC Committee for PracticeGuidelines (CPG), Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, antithrombotic drugs. Given the large number of patients treated Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, with PPIs and antithrombotic drugs, even a minor reduction in McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, the cardiovascular benefits of antithrombotic drugs may have sub- Tendera M, Torbicki A, Vahanian A, Windecker S; Document Reviewers,Hasdai D, Astin F, Astro¨m-Olsson K, Budaj A, Clemmensen P, Collet JP, stantial clinical impact. Accordingly, more studies are needed to Fox KA, Fuat A, Gustiene O, Hamm CW, Kala P, Lancellotti P, Maggioni AP, elucidate the clinical importance of the drug interactions described Merkely B, Neumann FJ, Piepoli MF, Van de Werf F, Verheugt F, Wallentin L.
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3. Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, No conclusive evidence to discourage PPIs with clopidogrel, Furberg CD, Johnson DA, Kahi CJ, Laine L, Mahaffey KW, Quigley EM, but evidence of benefit in terms of bleeding reduction. There- Scheiman J, Sperling LS, Tomaselli GF; ACCF/ACG/AHA. ACCF/ACG/AHA2010 expert consensus document on the concomitant use of proton pump inhi- fore, PPIs should be carefully prescribed if indicated.
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